Minimally invasive continuous glucose monitoring (CGM) sensors are becoming an increasingly adopted technology, especially for diabetic individuals needing insulin administrations. CGM sensors provide real-time insights into blood glucose (BG) dynamics and are equipped with hypo- and hyperglycemia alarms. According to research, these devices improve the efficiency of diabetes therapy and reduce hypoglycemia occurrences. Furthermore, patients are able to improve insulin dosage tuning and infusion.

The CGM systems generally rely on the glucose oxidation reaction technique. In this technique, a glucose-oxidase-doped platinum electrode is deposited on a needle, which is then inserted into the subcutaneous tissue to ignite and catalyze glucose oxidation. Using self-monitoring of blood glucose (SMBG) samples, the resulting electrical signal is converted to a glucose concentration through a calibration process.

CGM sensors provide a continuous trace of glucose through BG readings every 1 to 5 minutes. This mitigates the requirement of SMBG and significantly enhances the information on BG trends and fluctuations. Ever since the first prototype, CGM sensors have come a long way. The sensors these days also provide numerous smart features, such as alarms for delaying hypo- and hyperglycemic events. However, due to the cost and unacceptability, these devices represent only a small fraction of the total diabetic population.

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"First generation" CGM systems

CGM sensor devices were first proposed in 1999 after the U.S. Food and Drug Administration (FDA) approved their usage for medical professionals. The devices, however, had several limitations. The most notable one being low accuracy in measuring BG concentration values. There are several metrics to assess CGM accuracy, such as absolute relative difference and mean absolute relative difference (MARD). Among these, MARD is the most commonly used metric.

It was only in 2004 that the first company, called Medtronic MiniMed, successfully marketed a real-time CGM system for individual use: the Medtronic Real-Time Guardian. This system provided patients with a glucose concentration value every five minutes that lasted three days. It also had a sound alarm that went off whenever the glucose concentration level became too high or too low. The MARD of the Medtronic Real-Time Guardian was assessed to be 15%.

Soon after, Dexcom Inc. marketed the Dexcom SEVEN Plus. This CGM device had a longer lifetime, lasting up to seven days. Dexcom SEVEN Plus had slightly lower accuracy than the Medtronic Real-Time Guardian, at 16.7%. The same year, another CGM device called Abbott Freestyle Navigator (Abbott Diabetes Care, USA) was marketed. The device introduced a unique glucose sensor that could be worn up to five days, while achieving a MARD of 12.8%.

Compared to SMBG, these "first generation" CGM systems had extremely low accuracy. This issue presented as a significant barrier for their early adoption by both individuals and medical professionals.

Recent CGM systems

Over the last decade, CGM manufacturers have made significant progress in improving the accuracy of their devices. The first new-generation device, called the Medtronic Enlite, achieved a MARD of 13.6%. With an extended wear time, the device provided a more comfortable sensor with a reduced size and weight. Also, the CGM system's BG readings were saved for up to 10 hours. Soon after, Abbott also marketed their second-generation CGM system called Freestyle Navigator II. This device could provide BG readings every minute with a MARD rating of 12.3%. Similarly, in 2012, Dexcom launched the G4 Platinum CGM device, featuring an even smaller sensor.

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The company managed to reduce the MARD rating to 13%, with a wear time of seven days. Dexcom later managed to improve the rating further to 9% using new integrated sensor algorithms. In 2015, the same company launched G5 Mobile, which allowed BG data to be directly transmitted to the user's cell phone.

In 2016, the CGM system of the Freestyle Libre of MARD 11.4% was marketed by Abbott. It required no fingerstick testing and extended wear time up to 14 days. The Freestyle Libre is more of a flash glucose monitoring (FGM) device as it does not sound any alarms when BG falls out of the safe glycemic levels. Instead it measures the BG continuously, but displays the data only when the sensor is scanned against the receiver. It has also been the first CGM device that required no calibrations. Learning from this, Dexcom unveiled the G6 in 2017, which can be worn for 10 consecutive days without in vivo calibrations. Medtronic launched the Guardian Sensor 3 in the same year with MARD ratings of 10.6% and 9.1% when inserted in the abdomen and arm, respectively. The sensor is smaller, has a shorter startup time and has seven days of wear time.

Overall, the last decade has seen quite an improvement in CGM system features and wearability.

Upcoming CGM devices and their technological advances

Even though CGM systems are now widely accepted tools for intensive glucose control in type 1 diabetes mellitus patients, they provide several limitations. Some such limits are their non-linear response within the biologically relevant range, their reaction with active agents in the medium, their dependence on enzyme availability on the surface of the electrode and their delay in providing data. Active research will address and improve each of these features and come up with better CGM devices.

Keeping this in mind, Dexcom and Verily (based in California) got together in 2015 to develop a smaller and cheaper CGM patch to help with type 2 diabetes mellitus. Further, in 2018, Abbott launched the Freestyle Libre 2, which went on to secure the CE mark successfully while improving the Libre series by adding alarms.

Recently, optical glucose sensors have been proposed instead of glucose-oxidase technologies. These are simple in design, cheap and free from electromagnetic interference. These non-invasive optical glucose sensors are based on principles of fluorescence, Raman spectroscopy and near IR radiation. Eversense, the first implantable CGM device based on fluorescence, received the CE mark in 2016. It was launched by Senseonics and had a lifetime of 90 days with 11.4% MARD. The disadvantage to this device is that it needs to be surgically inserted.

A necessary feature in the upcoming CGM devices is data security. Data confidentiality and integration should be made a priority while designing these devices in order to prevent any cyberattacks. This thought has been proposed recently by the Diabetes Technology Society.

CGM technologies of today

Professional use

Professional CGM devices prescribed to patients are either in blind mode or owned by caregivers. When the device is in blind mode, glucose concentration data collection happens continuously but is not displayed in real-time to the patient. The caregiver can only review the data at the end of the day. Examples of such devices include Medtronic iPro2 and Abbott Freestyle LibrePro.

Personal use

Personal use CGM systems can alert users of possible hyper- or hypoglycemic levels in real-time, on a smartphone or portable receiver. Examples of such CGM systems include the Dexcom G5 Mobile, the Medtronic Enlite and Guardian, and the Senseonic Eversense. The new generation of CGM devices also have alerts, for example, the Freestyle Libre 2. Some of the systems are also equipped to share the data in real-time with parents, partners or other third parties.

Improvements in design structure and accuracy performance of CGM devices have led patients and caregivers to make treatment decisions without fingerstick confirmation. CGM devices such as the Freestyle Navigator II, the Freestyle Libre and the Dexcom G5 Mobile received the nonadjunctive label in Europe and later by the FDA. Despite this, fingerstick confirmatory tests are recommended by sensor companies, just in case.

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Uptake of CGM

In the early years of the last decade, CGM use was relatively low. They were expensive without insurance coverage, difficult to wear and experienced alarm fatigue and sensor inaccuracy. Recent developments in CGM technology have solved most of these problems. Now, most health insurance companies provide reimbursement for CGM devices to all T1DM and T2DM patients.

These improvements have seen a collective growth of CGM device usage across the U.S. and Europe, though the growth has been slow. One reason for this is that it is not entirely evident that CGM is actually beneficial for T2DM patients who are not on intensive insulin treatment, which represents the majority of the diabetic population.

Diabetic care institutions and colleges recommend the device for T1DM patients undergoing intensive insulin treatment who do not meet the CGM devices' glycemic target. T2DM patients with poor glycemic control are also recommended to use CGM devices. These devices are reported to be effective in cases of pregnant women with diabetes or gestational diabetes.

CGM in daily

Although clinicians and patients were apprehensive about using CGM devices in the early years of this technology, research and benefits, including published controlled clinical trials, have shown growth in device usage. These CGM sensor systems have been found to improve glycemic control, mitigate hypoglycemic episodes and reduce glycemic variability.

Improve glycemic control

Numerous controlled trials in patients adopting CGM versus a control group using SMBG have shown significant HbA1c reduction in CGM sensor users, around 41% to 60% of the time. Studies conducted across different populations, from children to adults and women with gestational diabetes, have all shown CGM as an effective tool to achieve glucose control in diabetics.

Hypoglycemic episode mitigation

CGM devices capture glycemic variations that cannot be seen by SMBG only. Real-time BG values and monitoring allow mitigation and even avoidance of hypoglycemia. This has significantly reduced short-term complications due to hyperglycemia, thereby improving individuals' quality of life.

Glycemic variability reduction

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Several studies were conducted to evaluate whether CGM usage could improve glycemic variability across different study conditions. All of them have shown a reduction in glycemic variability by the use of CGM devices. This unlocks the possibility of mitigating both hypo- and hyperglycemia conditions as well as various other complications that may arise.

Applications of real-time CGM data

Decision support systems

The development of decision support systems (DSS) has provided support to CGM users with proactive and personalized decisions in any scenario that may arise, thereby allowing them to react in a shorter time frame. Most DSSs already available are based on a predictive glucose module, an insulin suspension module and an adaptive insulin bolus calculator. Research has shown that DSSs are viable tools for improving diabetes treatment, and improvements are being made for them to come up with an optimal insulin treatment plan, thus helping patients with critical decision making.

Basal insulin attenuation

Devices integrating CGM sensors and insulin pumps have become available since 2006, such as Medtronic MiniMed Paradigm, Medtronic Paradigm Veo and MiniMed 530G. Many current systems also allow suspension of basal insulin infusion when CGM data are predicted to fall below a preset threshold in the coming 30 minutes. Such basal insulin suspension algorithms have been intensively studied and tested. Shreds of evidence from trials suggest the effectiveness of these algorithms in reducing hypoglycemia.

Closed-loop systems

AP closed-loop system tunes insulin pump injections based on CGM data, specifically the automatic basal insulin attenuation. The last decade has seen several studies on closed-loop systems, including proportional-integral-derivative controller, model predictive control, fuzzy logic controller. Hybrid closed-loop approaches are usually adopted, where insulin bolus administration is manual, while a control algorithm tunes basal insulin rate. An example of such an approach is the auto mode of MiniMed 670G, instead of the manual mode. Fully closed-loop systems, in which the users need not input their meals, are also being developed and tested. With this, there has been an increased interest in AP technology.

Future perspectives

CGM sensors have opened a new way for glucose monitoring in T1DM patients, especially as significant companies like Dextrom and Medtronic design cheaper and smaller alternatives with non-invasive systems. They are being used in diabetes therapy, activity trackers with improved glucose prediction algorithms and automatic basal insulin modulation.

FDA approval of integrated continuous glucose monitoring (iCGM) systems has allowed iCGM developers to market their products. These systems can integrate CGM data with insulin pumps, SMBG and mHealth app data. This allows for a better understanding of individual abnormal glucose events and tailoring a diabetes therapy better suited for the patient's lifestyle.

Finally, CGM data can be integrated with clinical records and a prescription registry to generate a digital ecosystem of diabetes data that could be used to develop state-of-the-art data analytics for personalized diabetes management and related complications.

About the author

Dr. Ratakonda received her medical degree from NTR University of Health Sciences of Vijaywada, India. She is an award-winning medical writer and has more than 15 years of medical research experience, as well as experience in patient care. She specializes in the development of scientific and educational content, and describes herself as motivated by new challenges in the medical field.